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Exposure and Response Analysis of Aleglitazar On View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Groningen University of Groningen Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes Koomen, Jeroen V; Heerspink, Hiddo J L; Schrieks, Ilse C; Schwartz, Gregory G; Lincoff, A Michael; Nicholls, Stephen J; Svensson, Anders; Wedel, Hans; Weichert, Arlette; Grobbee, Diederick E Published in: Diabetes obesity & metabolism DOI: 10.1111/dom.13862 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Koomen, J. V., Heerspink, H. J. L., Schrieks, I. C., Schwartz, G. G., Lincoff, A. M., Nicholls, S. J., ... Stevens, J. (2019). Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial. Diabetes obesity & metabolism. https://doi.org/10.1111/dom.13862 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 13-11-2019 Received: 26 June 2019 Revised: 2 August 2019 Accepted: 25 August 2019 DOI: 10.1111/dom.13862 ORIGINAL ARTICLE Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial Jeroen V. Koomen MSc1 | Hiddo J. L. Heerspink PhD1 | Ilse C. Schrieks PhD2 | Gregory G. Schwartz MD3 | A. Michael Lincoff MD4 | Stephen J. Nicholls PhD5 | Anders Svensson MD6 | Hans Wedel PhD7 | Arlette Weichert MD8 | Diederick E. Grobbee MD2 | Jasper Stevens PhD1 1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 2Julius Clinical & Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 3Cardiology Section, Rocky Mountain Regional VA Medical Center and University of Colorado School of Medicine, Colorado, Aurora 4C5Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 5Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia 6Clinical Development, Cardio Metabolism, F. Hoffmann-La Roche Ltd., Basel, Switzerland 7Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 8Product Development, Immunology, Infectious Disease and Ophthalmology (I2O), F. Hoffmann-La Roche Ltd., Basel, Switzerland Correspondence Hiddo J.L. Heerspink, PhD, Department of Abstract Clinical Pharmacy and Pharmacology, Aims: The AleCardio trial aimed to characterize the efficacy and safety of peroxisome University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box proliferator-activated receptor-αγ agonist aleglitazar in patients with type 2 diabetes 30 001, 9700 RB, Groningen, The mellitus and acute coronary syndrome. The trial terminated early because of futility Netherlands. Email: [email protected] and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Funding information Netherlands Organisation for Scientific Materials and Methods: The AleCardio trial enrolled 7226 patients to receive aleglitazar Research, Grant/Award Number: VIDI grant 150 μg or matching placebo on top of standard care. A population pharmacokinetic anal- (917.15.306); This work was funded by the NovoNordisk Foundation, Grant/Award ysis was conducted in a pharmacokinetic substudy to identify covariates that explained Number: NNF OC0013659 interindividual variability in exposure. Subsequently, the effect of these covariates on sur- Peer Review rogate and clinical outcomes was assessed in the full patient population. The peer review history for this article is Results: Concomitant administration of clopidogrel was identified as a covariate that available at https://publons.com/publon/10. 1111/dom.13862. influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC0–24)of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively). This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Diabetes Obes Metab. 2019;1–9. wileyonlinelibrary.com/journal/dom 1 2 KOOMEN ET AL. Conclusions: Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar. KEYWORDS aleglitazar, exposure response, peroxisome proliferator-activated receptor, PK-PD, randomized controlled trial 1 | INTRODUCTION symptomatic heart failure or hospitalization with a primary diagnosis of heart failure within the previous year, severe peripheral edema, an Peroxisome proliferator-activated receptor (PPAR)-γ receptors regu- estimated glomerular filtration rate (eGFR) of less than late glucose homeostasis, insulin sensitivity and lipid storage while 45 mL/min/1.73 m2, or treatment with another PPAR agonist. A total PPAR-α receptors regulate fatty acid β-oxidation and energy homeo- of 7226 patients at 720 sites in 26 countries were enrolled between stasis. Aleglitazar is a dual agonist of the PPAR-α and -γ receptors and February 2010 and May 2012. Between hospital discharge after ACS has been shown to improve glycaemic variables and lipid profile in and 12 weeks thereafter, patients were randomized in a double-blind, patients with type 2 diabetes mellitus.1,2 However, PPAR-γ activation 1:1 ratio to receive aleglitazar (150 μg per day) or matching placebo may lead to sodium and fluid retention, particularly in patients with on top of standard therapy. Patients were asked to take study medica- type 2 diabetes who are prone to sodium and fluid retention.3 tion at the same time of the day throughout the study, but a specific The AleCardio trial was designed to determine whether aleglitazar time of day or relation to meals was not specified. The primary effi- compared with placebo reduces cardiovascular morbidity and mortal- cacy endpoint was time to cardiovascular death, non-fatal myocardial ity among patients with type 2 diabetes mellitus and a recent acute infarction, or non-fatal stroke. Principal safety endpoints were hospi- coronary syndrome (ACS).4 The trial was terminated early because of talization caused by heart failure and changes in renal function. Effi- futility for efficacy and increased rates of congestive heart failure, cacy measures and hospitalization for heart failure were adjudicated bone fractures and gastrointestinal haemorrhage associated with by a blinded clinical events committee. Other adverse events of spe- aleglitazar.5 The increased rate of congestive heart failure is probably cial interest were edema, bone fractures, hypoglycaemia and malig- a result of sodium and fluid retention following PPAR-γ activation. nancies. Upon the recommendation of the data and safety monitoring Patients assigned to aleglitazar received a fixed dose of 150 μg board, the trial was terminated in July 2013 with a median follow-up daily. It is unknown whether increased exposure to aleglitazar contrib- of 2 years because of futility for efficacy and increased rates of safety uted to the safety findings in the trial. The aim of the current study endpoints with aleglitazar. was therefore to characterize the interindividual variation in exposure In a pharmacokinetic substudy, plasma samples were collected in to aleglitazar, to determine the factors associated with aleglitazar 515 of 3616 patients treated with aleglitazar. In this substudy, exposure, and to assess the association between aleglitazar exposure patients were divided into two groups with different pharmacokinetic and safety and efficacy measures. sampling schemes. In the first group (n = 117), a total of four samples were collected at predose and between 30–120, 121–180 and 181–240 minutes after administration of aleglitazar at a single study 2 | MATERIALS
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